Abstract
Background
The selection of P2Y12 inhibitors for acute coronary syndrome patients after percutaneous coronary intervention (PCI) remains controversial among East Asian patients.
Objectives
This study aimed to identify the optimal P2Y12 inhibitor selection for the East Asian population carrying CYP2C19 loss-of-function (LOF) alleles based on the Global Registry of Acute Coronary Events (GRACE) score.
Methods
Between March 2016 and March 2019, a cohort of 8683 patients diagnosed with acute coronary syndrome who survived PCI were enrolled in this study. All patients carried the LOF allele and could calculate GRACE scores. The primary outcome was ischemic events (cardiac death, nonfatal myocardial infarction, and ischemic stroke) within 12 months. Secondary outcomes included the components of the primary outcome, all-cause mortality, Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 bleeding events, and BARC types 3 and 5 bleeding events. The propensity score matching method was used to balance the baseline characteristics of patients. The Kaplan–Meier/log-rank test was adopted for the result analysis, and Cox regression was employed for adjusting for confounding factors.
Results
The low-risk group comprised 5496 patients (63.3%), while the intermediate- to high-risk group included 3187 patients (36.7%) in the study population stratified by GRACE scores. The follow-up results revealed that in patients at low risk, clopidogrel and ticagrelor had comparable effects in preventing ischemic events. However, ticagrelor use was associated with a higher risk of BARC types 2, 3, and 5 bleeding events (hazard ratio [HR], 2.08; 95% CI, 1.43-3.02; P < .001) and BARC types 3 and 5 bleeding events (HR, 2.69; 95% CI, 1.57-4.63; P < .001) compared with clopidogrel use. In patients at intermediate to high risk, ticagrelor treatment was associated with a lower risk of stroke (HR, 0.18; 95% CI, 0.04-0.82; P = .026), while the risk of ischemic events or bleeding was comparable between the 2 treatment groups.
Conclusion
These real-world data on East Asian patients with CYP2C19 LOF alleles suggest that GRACE risk stratification may help differentiate ischemic and bleeding risks post-PCI.
Keywords: acute coronary syndrome, CYP2C19 loss-of-function alleles, dual antiplatelet therapy, percutaneous coronary intervention, The Global Registry of Acute Coronary Events
Graphical abstract
Essentials
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East Asian PCI patients’ P2Y12 inhibitor use often differs from guidelines.
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Clopidogrel vs ticagrelor were compared in ACS patients with CYP2C19 LOF alleles using GRACE scores.
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Clopidogrel lowered bleeding risk in patients with low GRACE scores; ticagrelor reduced stroke in patients with mid-high GRACE scores.
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GRACE scores may guide P2Y12 inhibitor choice in post-PCI patients with CYP2C19 LOF alleles.
1. Introduction
Cardiovascular disease is one of the leading causes of mortality worldwide [1], and dual antiplatelet therapy (DAPT) is the cornerstone of treatment for patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) [[2], [3], [4], [5]]. The 2023 European Society of Cardiology (ESC) guidelines clearly recommend ticagrelor as the preferred drug for P2Y12 inhibitors [6]. However, for Chinese patients, the risk of bleeding is notably high, and considerations regarding the CYP2C19 genotype are often overlooked [[7], [8], [9], [10]].
Clopidogrel, as a P2Y12 inhibitor, needs to be metabolized into active metabolites through the hepatic cytochrome P450 (CYP) system to exert antiplatelet effects. Based on CYP2C19 genotypes, patients can be classified as rapid metabolizers (carrying no CYP2C19 loss-of-function [LOF] alleles), intermediate metabolizers (carrying 1 LOF allele), and poor metabolizers (carrying 2 LOF alleles [11]). CYP2C19 LOF alleles (eg, CYP2C19∗2 and CYP2C19∗3) are genetic variants associated with reduced or absent enzyme activity. In contrast to clopidogrel, ticagrelor’s antiplatelet effect is independent of the CYP2C19 genotype, as it is metabolized via CYP3A4/5 and does not require enzymatic activation [12]. Different genotypes affect the formation of active metabolites of clopidogrel in patients, thus affecting its efficacy and safety [13]. Patients with CYP2C19 LOF alleles may not be able to obtain adequate antiplatelet effects from standard doses of clopidogrel, thereby increasing the risk of ischemic events [14]. Despite these considerations, routine genetic testing to guide the selection of P2Y12 inhibitors is not commonly recommended in most clinical guidelines. However, the 2024 American Heart Association scientific statement recommends CYP2C19 genetic testing before oral P2Y12 inhibitors [15].
There exists considerable heterogeneity in the clinical manifestation of patients with ACS, leading to significant variations in prognosis. Therefore, early and comprehensive risk assessment is essential for the appropriate selection of postoperative antiplatelet agents. The Global Registry of Acute Coronary Events (GRACE) scoring system is a guideline-recommended risk stratification tool that is widely used in clinical practice to assess ischemic risk of patients [16]. However, this scoring system does not incorporate CYP2C19 genotype. Therefore, it is necessary to investigate whether combining GRACE risk stratification could optimize antiplatelet therapy selection for ACS patients carrying CYP2C19 LOF alleles after PCI.
This study aimed to explore the optimal selection of P2Y12 inhibitors for ACS patients with CYP2C19 LOF alleles after PCI in the real world by examining the relationship between taking ticagrelor or clopidogrel and different clinical outcomes.
2. Methods
2.1. Data sources and study population
The subjects of this study were derived from a large-scale, prospective, single-center observational cohort study, which included patients undergoing PCI treatment at The General Hospital of Northern Theater Command from March 2016 to March 2019. The inclusion criteria comprised patients diagnosed with ACS who underwent PCI; age ≥18 years; DAPT with clopidogrel or ticagrelor; CYP2C19 genotyping using DNA microarray technology, with results categorized as intermediate/poor metabolizer phenotypes according to Clinical Pharmacogenetics Implementation Consortium guidelines [17]. The exclusion criteria were CYP2C19 rapid metabolizer genotype, absence of genotype testing, inability to calculate the GRACE score, changing P2Y12 inhibitors during hospitalization, loss to follow-up, and expected patient lifespan of less than 12 months (Supplementary Figure).
For patients with ACS undergoing PCI, current clinical guidelines recommend aspirin plus a P2Y12 receptor inhibitor as the standard treatment regimen. During the research period, the selection of clopidogrel and ticagrelor was based on clinician assessment of bleeding/ischemic risk, comorbidities, and considerations regarding medication guidelines. During this period, CYP2C19 genotyping was not routinely used as a basis for clinical decision-making. All patients were discharged with aspirin (100 mg daily) in combination with either clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily) for a minimum duration of 12 months. All clopidogrel-treated patients received standard 75 mg daily maintenance dosing regardless of CYP2C19 metabolizer status. Based on CYP2C19 genotype, patients who carry 1 CYP2C19∗1 allele along with 1 CYP2C19∗2 or CYP2C19∗3 allele were classified as intermediate metabolizers, while those with 2 alleles (either CYP2C19∗2/∗2, ∗2/∗3, or ∗3/∗3) were identified as poor metabolizers. Patients were followed up at 3, 6, 9, and 12 months after discharge through telephone interviews conducted by trained personnel. This research received ethical approval from The General Hospital of Northern Theater Command with a waiver of informed consent requirements.
The study strictly adhered to all standards of the Declaration of Helsinki. Data were proactively collected during the patients’ hospital stay and entered the CV-NET system at Crealife Technology in Beijing, China. Collected data included demographics, medical history, risk factors, laboratory findings, surgical factors, and medications.
2.2. Definitions and outcomes
The primary outcome of this study was the occurrence of ischemic events within 12 months following discharge, defined as a composite of cardiac death, nonfatal myocardial infarction (MI), and ischemic stroke. Secondary outcomes included all components of the primary outcome, all-cause mortality, Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 bleeding events, and BARC types 3 and 5 bleeding events.
Cardiac death was determined based on either imaging evidence (eg, computed tomography/magnetic resonance imaging) or fulfillment of the World Health Organization definition of cardiac death after excluding other causes [18]. Nonfatal MI was diagnosed according to European Society of Cardiology (ESC)/American College of cardiology (ACC) criteria, supported by dynamic troponin changes, ischemic symptoms, and electrocardiogram/imaging findings [19]. Ischemic stroke was defined as a sudden onset of neurological deficits (eg, vertigo, numbness, aphasia, or dysarthria) caused by cerebral vascular lesions (such as embolism or thrombosis), with symptoms persisting for >24 hours [20]. The definition of different types of BARC bleeding was based on the standard definitions outlined in Supplementary Table S1 [21]. An experienced panel reviewed and adjudicated all events according to the above definitions.
The GRACE score used in this study is an important tool for clinicians to assess the risk of long-term ischemic events in patients [16]. Concrete calculations are provided in Supplementary Table S2. The scoring system incorporates a range of variables before patient discharge (age, heart rate, systolic blood pressure, initial serum creatinine, elevated cardiac enzyme/marker levels, congestive heart failure, whether the patient has undergone in-hospital PCI or in-hospital coronary artery bypass grafting, a history of MI, and ST-segment depression). All in-hospital data were collected retrospectively from routine clinical documentation. According to the management guidelines recommended by the ESC, patients are classified as low risk (GRACE score ≤88) and intermediate to high risk (GRACE score >88) based on their GRACE scores [22].
2.3. Statistical analysis
Follow-up began at discharge after the initial PCI hospitalization. Time to event was calculated from baseline until the first occurrence of primary outcome, last contact date (for patients lost to follow-up), or 12-month study completion. This approach was uniformly applied to all participants. Continuous variables were expressed as the mean ± SD and were compared by Student’s t-test. Categorical variables were expressed as frequency and percentage and were compared by chi-square test or Fisher’s exact test. We performed separate propensity score modeling and matching for low-risk and intermediate- to high-risk GRACE groups. We conducted 1:1 propensity score matching (PSM) between ticagrelor-treated and clopidogrel-treated patients using nearest-neighbor matching with a 0.2 SD caliper. The propensity score model incorporated all the baseline variables in Table 1. After balanced treatment, the model was used to predict the effect of ticagrelor or clopidogrel on clinical outcomes at discharge. Kaplan–Meier curves and log-rank tests were utilized to compare the primary and secondary outcomes between clopidogrel and ticagrelor groups in patients with different GRACE risk groups before and after PSM. The hazard ratios (HRs) and 95% CIs were calculated based on the Cox proportional hazards regression model, which was adjusted for age, sex, hypertension, diabetes, previous MI, previous PCI, previous stroke, smoking history, ACS subtypes, estimated glomerular filtration rate, CYP2C19 genotype, left ventricular ejection fraction, anemia, procedural characteristics, and medical treatment at discharge. All tests were 2-sided. P values < .05 were considered statistically significant. Statistical analyses were performed using R version 4.2.2 (R Core Team).
Table 1.
Baseline characteristics of clopidogrel vs ticagrelor groups in low-risk patients (Global Registry of Acute Coronary Events score ≤ 88) carrying CYP2C19 loss-of-function alleles.
| Characteristics | Before propensity score matching |
After propensity score matching |
||||
|---|---|---|---|---|---|---|
| Clopidogrel (n = 3221) | Ticagrelor (n = 2275) | P value | Clopidogrel (n = 1849) | Ticagrelor (n = 1849) | P value | |
| Age, y | 56.65 ± 8.26 | 54.55 ± 8.62 | <.001 | 55.17 ± 8.26 | 55.15 ± 8.36 | .946 |
| Male | 2387 (74.11) | 1855 (81.54) | <.001 | 1478 (79.94) | 1472 (79.61) | .806 |
| Hypertension | 1944 (60.35) | 1325 (58.27) | .12 | 1088 (58.84) | 1099 (59.44) | .71 |
| Diabetes | 945 (29.41) | 691 (30.47) | .40 | 561 (30.34) | 554 (29.96) | .80 |
| Previous MI | 281 (8.75) | 233 (10.25) | .06 | 170 (9.19) | 172 (9.30) | .91 |
| Previous stroke | 457 (14.20) | 188 (8.27) | <.001 | 150 (8.11) | 168 (9.09) | .29 |
| Previous PCI | 497 (15.43) | 363 (15.97) | .587 | 267 (14.44) | 264 (14.28) | .888 |
| Smoking history | <.001 | .248 | ||||
| None | 1330 (41.42) | 797 (35.17) | 690 (37.32) | 674 (36.45) | ||
| Current smoker | 1453 (45.25) | 1209 (53.35) | 921 (49.81) | 964 (52.14) | ||
| Ex smoker | 428 (13.33) | 260 (11.47) | 238 (12.87) | 211 (11.41) | ||
| ACS subtypes | <.001 | .84 | ||||
| UA | 2175 (67.53) | 1347 (59.21) | 1133 (61.28) | 1149 (62.14) | ||
| NSTEMI | 476 (14.78) | 381 (16.75) | 313 (16.93) | 302 (16.33) | ||
| STEMI | 570 (17.70) | 547 (24.04) | 403 (21.80) | 398 (21.53) | ||
| Anemia | 287 (8.91) | 192 (8.44) | .54 | 155 (8.38) | 153 (8.27) | .905 |
| eGFR, mL/min per 1.73 m2 | 97.79 ± 24.13 | 99.89 ± 22.27 | <.001 | 99.47 ± 21.85 | 99.87 ± 22.26 | .588 |
| CYP2C19 genotype | <.001 | .50 | ||||
| Intermediate metabolizer | 2734 (84.88) | 1616 (71.03) | 1443 (78.04) | 1426 (77.12) | ||
| Poor metabolizer | 48 7 (15.12) | 659 (28.97) | 406 (21.96) | 423 (22.88) | ||
| LVEF, % | 60.18 ± 7.48 | 59.11 ± 7.95 | <.001 | 59.46 ± 7.73 | 59.63 ± 7.68 | .548 |
| Procedural information | ||||||
| Transradial access | 3064 (95.13) | 2160 (94.95) | .76 | 1769 (95.67) | 1770 (95.73) | .935 |
| Coronary arteries treated | ||||||
| LM | 88 (2.73) | 154 (6.77) | <.001 | 75 (4.06) | 83 (4.49) | .515 |
| LAD | 1759 (54.61) | 1286 (56.53) | .159 | 1024 (55.38) | 1037 (56.08) | .667 |
| LCX | 770 (23.91) | 535 (23.52) | .738 | 448 (24.23) | 449 (24.28) | .969 |
| RCA | 1201 (37.29) | 815 (35.82) | .268 | 699 (37.80) | 676 (36.56) | .43 |
| No. of stents | 1.50 ± 0.82 | 1.69 ± 0.94 | <.001 | 1.71 ± 0.82 | 1.70 ± 0.84 | .69 |
| Total length of stents, mm | 41.99 ± 24.11 | 47.88 ± 27.53 | <.001 | 46.29 ± 26.28 | 45.73 ± 25.62 | .51 |
| Average stent diameters, mm | 3.05 ± 0.63 | 3.12 ± 1.12 | .007 | 3.07 ± 0.74 | 3.07 ± 0.41 | .92 |
| Medical treatment at discharge | ||||||
| Aspirin | 3180 (98.73) | 2232 (98.11) | .066 | 1818 (98.32) | 1814 (98.11) | .619 |
| Statins | 3009 (93.42) | 2107 (92.62) | .248 | 1716 (92.81) | 1712 (92.59) | .80 |
| ACEI/ARB | 2111 (65.54) | 1506 (66.20) | .61 | 1212 (65.55) | 1220 (65.98) | .78 |
| β-blocker | 2224 (69.05) | 1603 (70.46) | .26 | 1304 (70.52) | 1289 (69.71) | .59 |
| PPIs | 1269 (39.40) | 814 (35.78) | .007 | 656 (35.48) | 678 (36.67) | .45 |
Values are mean ± SD or n (%).
ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; LAD, left anterior descending branch; LCX, left circumflex branch; LM, left main coronary artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.
3. Results
3.1. Overview of the study population
From March 2016 to March 2019, a total of 21,531 patients with ACS who underwent PCI were enrolled in this study. Following a comprehensive screening process, 8683 patients with complete GRACE scores at discharge and identified as intermediate or poor metabolizers of CYP2C19 genotypes were included in the final analysis. Among these patients, 3221 (58.6%) with low-risk GRACE scores were prescribed clopidogrel at discharge, while 2275 (41.4%) received ticagrelor. Among patients with intermediate- to high-risk GRACE scores, 2230 (70.0%) were treated with clopidogrel, whereas 957 (30.0%) were prescribed ticagrelor.
3.2. Clopidogrel vs ticagrelor in low-risk (GRACE score ≤ 88) and CYP2C19 intermediate/poor metabolizer patients
As shown in Table 1, patients in the clopidogrel group were generally older than those in the ticagrelor group, with a higher proportion of females and a greater prevalence of comorbidities such as hypertension, stroke, and anemia. In terms of procedural characteristics, lesions affecting the left mainstem coronary artery as the target vessel were more prevalent in the ticagrelor cohort, and these patients received a greater number of stents, with a longer total stent length and a larger average stent diameter. Furthermore, patients in the clopidogrel group were more often prescribed proton pump inhibitor medications at discharge.
Before PSM, the hazard of ischemic events (cardiovascular death, nonfatal MI, or ischemic stroke) was marginally lower with ticagrelor vs clopidogrel (HR, 0.64; 95% CI, 0.41-1.00; P = .048). Ticagrelor treatment was associated with a lower risk of ischemic stroke than clopidogrel (HR, 0.36; 95% CI, 0.17-0.79; P = .01). However, compared with the clopidogrel group, the ticagrelor group had a significantly increased risk of BARC types 2, 3, and 5 bleeding events (HR, 1.87; 95% CI, 1.39-2.50; P < .001) and BARC types 3 and 5 bleeding events (HR, 2.06; 95% CI, 1.38-3.06; P < .001). No significant differences were noted in the rates of cardiovascular death, nonfatal MI, and all-cause mortality between the 2 groups before PSM (Table 2). Kaplan–Meier curves are shown in Figure 1.
Table2.
Clinical outcomes between the clopidogrel and ticagrelor groups in low-risk patients (Global Registry of Acute Coronary Events score ≤ 88).
| Outcomes | Before propensity score matching |
After propensity dcore matching |
||||||
|---|---|---|---|---|---|---|---|---|
| Clopidogrel (n = 3221) | Ticagrelor (n = 2275) | Adjusted HRa (95% CI) | P value | Clopidogrel (n = 1849) | Ticagrelor (n = 1849) | Adjusted HRa (95% CI) | P value | |
| Ischemic eventsb | 62 (1.92) | 28 (1.23) | 0.64 (0.41-1.00) | .048 | 37 (2.00) | 26 (1.41) | 0.70 (0.42-1.16) | .16 |
| Cardiac death | 20 (0.62) | 15 (0.66) | 1.06 (0.54-2.08) | .858 | 12 (0.65) | 13 (0.70) | 1.09 (0.50-2.38) | .838 |
| Nonfatal MI | 14 (0.43) | 6 (0.26) | 0.61 (0.23-1.58) | .306 | 11 (0.59) | 6 (0.32) | 0.55 (0.20-1.47) | .23 |
| Stroke | 31 (0.96) | 8 (0.35) | 0.36 (0.17-0.79) | .01 | 17 (0.92) | 8 (0.43) | 0.47 (0.20-1.09) | .077 |
| All-cause mortality | 32 (0.99) | 24 (1.05) | 1.06 (0.63-1.80) | .82 | 16 (0.87) | 21 (1.14) | 1.32 (0.69-2.52) | .409 |
| BARC types 2, 3, and 5 bleeding | 80 (2.48) | 104 (4.57) | 1.87 (1.39-2.50) | <.001 | 41 (2.22) | 84 (4.54) | 2.08 (1.43-3.02) | <.001 |
| BARC types 3 and 5 bleeding | 41 (1.27) | 59 (2.59) | 2.06 (1.38-3.06) | <.001 | 18 (0.97) | 48 (2.60) | 2.69 (1.57-4.63) | <.001 |
Values are n (%).
HR, hazard ratio; BARC, Bleeding Academic Research Consortium; MI, myocardial infarction.
The Cox proportional hazards model is adjusted for age, sex, hypertension, diabetes, previous MI, previous percutaneous coronary intervention, previous stroke, smoking history, acute coronary syndrome subtypes, estimated glomerular filtration rate, CYP2C19 genotype, left ventricular ejection fraction, anemia, procedural characteristics, and medical treatment at discharge.
Ischemic events were defined as a composite of cardiovascular death, nonfatal MI, and ischemic stroke.
Figure 1.
Kaplan–Meier curves for clinical outcomes in low-risk patients (Global Registry of Acute Coronary Events score ≤ 88) before propensity score matching. Cumulative incidences according to follow-up time between clopidogrel group and ticagrelor group for (A) primary outcome, ischemic events (defined as a composite of cardiac death, nonfatal myocardial infarction, and stroke) in low-risk patients, (B) all-cause death in low-risk patients, (C) Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding events in low-risk patients, and (D) BARC types 3 or 5 bleeding events in low-risk patients. HR, hazard ratio.
After PSM, the risk of BARC types 2, 3, and 5 bleeding events (HR, 2.08; 95% CI, 1.43-3.02; P < .001) and BARC types 3 and 5 bleeding events (HR, 2.69; 95% CI, 1.57-4.63; P < .001) in patients treated with ticagrelor remained significantly higher than in the clopidogrel group. There was no significant difference in ischemic events and all-cause mortality between the 2 groups. After PSM, no significant difference was observed between the 2 treatment groups for any individual component of ischemic events (Table 2). Kaplan–Meier curves are shown in Figure 2.
Figure 2.
Kaplan–Meier curves for clinical outcomes in low-risk patients (Global Registry of Acute Coronary Events score ≤ 88) after propensity score matching (PSM). Cumulative incidences according to follow-up time between the clopidogrel group and the ticagrelor group after PSM for the (A) primary outcome, ischemic events (defined as a composite of cardiac death, nonfatal myocardial infarction, and stroke) in low-risk patients, (B) all-cause death in low-risk patients, (C) Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding events in low-risk patients, and (D) BARC types 3 or 5 bleeding events in low-risk patients. The PSM model was adjusted for age, sex, hypertension, diabetes, previous myocardial infarction, previous percutaneous coronary intervention, previous stroke, smoking history, acute coronary syndrome subtypes, estimated glomerular filtration rate, CYP2C19 genotype, left ventricular ejection fraction, anemia, procedural characteristics, and medical treatment at discharge.HR, hazard ratio.
3.3. Clopidogrel vs ticagrelor in intermediate-to-high risk (GRACE score > 88) and CYP2C19 intermediate/poor metabolizer patients
Patients treated with ticagrelor were more likely to be younger, male, and smokers compared with those receiving clopidogrel. In terms of procedural characteristics, the ticagrelor group exhibited a higher prevalence of left main coronary artery lesions, as well as longer total stent lengths and greater numbers of implanted stents. Additionally, patients discharged with ticagrelor were less likely to be prescribed proton pump inhibitors (Table 3). After PSM, the baseline characteristics were balanced between the 2 groups (Table 3).
Table 3.
Baseline characteristics of clopidogrel vs ticagrelor groups in intermediate-to-high risk patients (Global Registry of Acute Coronary Events score > 88) carrying CYP2C19 loss-of-function alleles.
| Characteristics | Before propensity score matching |
After propensity score matching |
||||
|---|---|---|---|---|---|---|
| Clopidogrel (n = 2230) | Ticagrelor (n = 957) | P value | Clopidogrel (n = 826) | Ticagrelor (n = 826) | P value | |
| Age, y | 70.34 ± 7.16 | 65.75 ± 5.99 | <.001 | 66.42 ± 6.65 | 66.36 ± 5.61 | .85 |
| Male | 1386 (62.15) | 716 (74.82) | <.001 | 591 (71.55) | 602 (72.88) | .546 |
| Hypertension | 1452 (65.14) | 586 (61.23) | .035 | 516 (62.47) | 515 (62.35) | .96 |
| Diabetes | 715 (32.11) | 313 (32.84) | .68 | 268 (32.45) | 266 (32.20) | .916 |
| Previous MI | 494 (22.26) | 244 (25.52) | .046 | 193 (23.37) | 195 (23.61) | .908 |
| Previous stroke | 453 (20.35) | 119 (12.46) | <.001 | 106 (12.83) | 108 (13.08) | .88 |
| Previous PCI | 513 (23.04) | 217 (22.70) | .836 | 167 (20.22) | 176 (21.31) | .585 |
| Smoking history | <.001 | .57 | ||||
| None | 1175 (52.76) | 435 (45.50) | 383 (46.37) | 375 (45.40) | ||
| Current smoker | 749 (33.63) | 384 (40.17) | 334 (40.44) | 327 (39.59) | ||
| Ex smoker | 303 (13.61) | 137 (14.33) | 109 (13.20) | 124 (15.01) | ||
| ACS subtypes | <.001 | .816 | ||||
| UA | 1146 (51.39) | 407 (42.53) | 364 (44.07) | 376 (45.52) | ||
| NSTEMI | 432 (19.37) | 200 (20.90) | 177 (21.43) | 169 (20.46) | ||
| STEMI | 652 (29.24) | 350 (36.57) | 285 (34.50) | 281 (34.02) | ||
| Anemia | 599 (26.87) | 195 (20.38) | <.001 | 169 (20.46) | 169 (20.46) | >.999 |
| eGFR, mL/min per 1.73 m2 | 81.31 ± 24.36 | 86.24 ± 22.75 | <.001 | 86.49 ± 24.58 | 86.46 ± 22.79 | .98 |
| CYP2C19 genotype | <.001 | .87 | ||||
| Intermediate metabolizer | 1841 (82.56) | 667 (69.70) | 594 (71.91) | 591 (71.55) | ||
| Poor metabolizer | 389 (17.44) | 290 (30.30) | 232 (28.09) | 235 (28.45) | ||
| LVEF, % | 56.69 ± 9.19 | 55.06 ± 9.96 | <.001 | 55.44 ± 9.41 | 55.59 ± 9.78 | .77 |
| Procedural characteristics | ||||||
| Trans radial access | 2028 (90.94) | 863 (90.18) | .496 | 760 (92.01) | 750 (90.80) | .38 |
| Coronary arteries treated | ||||||
| LM | 131 (5.87) | 85 (8.88) | .002 | 66 (7.99) | 70 (8.47) | .72 |
| LAD | 1122 (50.31) | 515 (53.81) | .07 | 435 (52.66) | 441 (53.39) | .767 |
| LCX | 495 (22.20) | 231 (24.14) | .23 | 216 (26.15) | 209 (25.30) | .69 |
| RCA | 918 (41.17) | 336 (35.11) | .001 | 287 (34.75) | 296 (35.84) | .64 |
| No. of stents | 1.53 ± 0.89 | 1.63 ± 0.92 | .003 | 1.67 ± 0.83 | 1.73 ± 0.86 | .145 |
| Total length of stents, mm | 43.98 ± 25.55 | 46.50 ± 25.81 | .01 | 44.46 ± 25.08 | 46.28 ± 25.72 | .145 |
| Average stent diameters, mm | 3.02 ± 0.81 | 3.00 ± 0.37 | .409 | 2.99 ± 0.38 | 3.00 ± 0.37 | .667 |
| Medical treatment at discharge | ||||||
| Aspirin | 2171 (97.35) | 940 (98.22) | .14 | 807 (97.70) | 811 (98.18) | .488 |
| Statins | 2066 (92.65) | 888 (92.79) | .886 | 764 (92.49) | 769 (93.10) | .63 |
| ACEI/ARB | 1434 (64.30) | 651 (68.03) | .04 | 542 (65.62) | 557 (67.43) | .43 |
| β-blocker | 1462 (65.56) | 676 (70.64) | .005 | 568 (68.77) | 578 (69.98) | .59 |
| PPIs | 882 (39.55) | 347 (36.26) | .08 | 296 (35.84) | 304 (36.80) | .68 |
Values are mean ± SD or n (%).
ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; LAD, left anterior descending branch; LCX, left circumflex branch; LM, left main coronary artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.
Prior to PSM, there was no significant difference in the risk of ischemic events between the clopidogrel group and the ticagrelor group (HR, 0.77; 95% CI, 0.50-1.19; P = .246). However, ticagrelor use was associated with a lower risk of stroke events compared with clopidogrel use (HR, 0.19; 95% CI, 0.05-0.82; P = .026). There was no significant difference in all-cause mortality between the 2 groups (HR, 0.80; 95% CI, 0.49-1.30; P = .366). Although the risk of BARC types 2, 3, and 5 bleeding events (HR, 1.23; 95% CI, 0.86-1.76; P = .26) and BARC types 3 and 5 bleeding events (HR, 1.26; 95% CI, 0.80-1.97; P = .32) were slightly higher in the ticagrelor group than in the clopidogrel group, these differences were not statistically significant. Prior to PSM, there were no significant differences between the 2 groups in cardiac death and nonfatal MI (Table 4). Kaplan–Meier curves are shown in Figure 3.
Table 4.
Clinical outcomes between clopidogrel and ticagrelor groups in intermediate-to-high risk patients (Global Registry of Acute Coronary Events score > 88).
| Outcomes | Before propensity score matching |
After propensity score matching |
||||||
|---|---|---|---|---|---|---|---|---|
| Clopidogrel (n = 2230) | Ticagrelor (n = 957) | Adjusted HRa (95% CI) | P value | Clopidogrel (n = 826) | Ticagrelor (n = 826) | Adjusted HRa (95% CI) | P value | |
| Ischemic eventsb | 81 (3.63) | 27 (2.82) | 0.77 (0.50-1.19) | .246 | 28 (3.39) | 21 (2.54) | 0.75 (0.42-1.31) | .31 |
| Cardiac death | 44 (1.97) | 20 (2.09) | 1.06 (0.62-1.79) | .836 | 11 (1.33) | 15 (1.82) | 1.36 (0.63-2.97) | .43 |
| Nonfatal MI | 15 (0.67) | 6 (0.63) | 0.93 (0.36-2.40) | .88 | 6 (0.73) | 5 (0.61) | 0.83 (0.25-2.73) | .76 |
| Stroke | 24 (1.08) | 2 (0.21) | 0.19 (0.05-0.82) | .026 | 11 (1.33) | 2 (0.24) | 0.18 (0.04-0.82) | .026 |
| All-cause mortality | 64 (2.87) | 22 (2.30) | 0.80 (0.49-1.30) | .366 | 19 (2.30) | 17 (2.06) | 0.90 (0.47-1.72) | .74 |
| BARC types 2, 3, and 5 bleeding | 86 (3.86) | 45 (4.70) | 1.23 (0.86-1.76) | .26 | 28 (3.39) | 36 (4.36) | 1.29 (0.79-2.12) | .306 |
| BARC types 3 and 5 bleeding | 54 (2.42) | 29 (3.03) | 1.26 (0.80-1.97) | .32 | 20 (2.42) | 24 (2.91) | 1.21 (0.67-2.18) | .537 |
Values are n (%).
HR, hazard ratio; BARC, Bleeding Academic Research Consortium; MI, myocardial infarction.
The Cox proportional hazards model is adjusted for age, sex, hypertension, diabetes, previous MI, previous percutaneous coronary intervention, previous stroke, smoking history, acute coronary syndrome subtypes, estimated glomerular filtration rate, CYP2C19 genotype, left ventricular ejection fraction, anemia, procedural characteristics, and medical treatment at discharge.
Ischemic events were defined as a composite of cardiovascular death, nonfatal MI, and ischemic stroke.
Figure 3.
Kaplan–Meier curves for clinical outcomes in intermediate-to-high risk patients (Global Registry of Acute Coronary Events score > 88) before propensity score matching. Cumulative incidences according to follow-up time between clopidogrel group and ticagrelor group for the (A) primary outcome, ischemic events (defined as a composite of cardiac death, nonfatal myocardial infarction, and stroke) in intermediate-to-high risk patients, (B) stroke in intermediate-to-high risk patients, (C) Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding events in intermediate-to-high risk patients, and (D) BARC types 3 or 5 bleeding events in intermediate-to-high risk patients. HR, hazard ratio
After PSM, ticagrelor use showed numerically higher but nonsignificant hazards for both BARC types 2, 3, and 5 bleeding events (HR, 1.29; 95% CI, 0.79-2.12; P = .306) and BARC types 3 and 5 bleeding events (HR, 1.21; 95% CI, 0.67-2.18; P = .537) compared with clopidogrel use. However, ticagrelor treatment was associated with a significantly lower risk of stroke (HR, 0.18; 95% CI, 0.04-0.82; P = .026). Furthermore, no significant differences were observed in ischemic events and all-cause mortality between the 2 groups. Kaplan–Meier curves are shown in Figure 4.
Figure 4.
Kaplan–Meier curves for clinical outcomes in intermediate-to-high risk patients (Global Registry of Acute Coronary Events score > 88) after propensity score matching (PSM). Cumulative incidences according to follow-up time between clopidogrel group and ticagrelor group after PSM for the (A) primary outcome, ischemic events (defined as a composite of cardiac death, nonfatal myocardial infarction, and stroke) in intermediate-to-high risk patients, (B) stroke in intermediate-to-high risk patients, (C) Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding events in intermediate-to-high risk patients, and (D) BARC types 3 or 5 bleeding events in intermediate-to-high risk patients. The PSM model was adjusted for age, sex, hypertension, diabetes, previous myocardial infarction, previous percutaneous coronary intervention, previous stroke, smoking history, acute coronary syndrome subtypes, estimated glomerular filtration rate, CYP2C19 genotype, left ventricular ejection fraction, anemia, procedural characteristics, and medical treatment at discharge.HR, hazard ratio.
4. Discussion
In this real-world study, we compared the incidence of ischemic and bleeding events between 2 treatment groups of ACS patients carrying CYP2C19 LOF alleles who underwent PCI: those receiving ticagrelor vs those receiving clopidogrel. The main findings are as follows: a) for ACS patients carrying CYP2C19 LOF alleles, integrating GRACE risk scores may optimize antiplatelet therapy selection after PCI; b) in patients with low GRACE risk scores, ticagrelor therapy was associated with an increased risk of BARC types 2, 3, and 5 bleeding events and BARC types 3 and 5 bleeding events compared with clopidogrel therapy; c) for patients with intermediate to high GRACE scores, clopidogrel use was associated with a higher risk of stroke compared with ticagrelor, while bleeding event rates were similar between the 2 treatment groups. These findings remained consistent both before and after PSM.
Currently, most guidelines clearly indicate that for ACS patients who have undergone PCI, combining aspirin and P2Y12 receptor inhibitors is a fundamental and critical treatment strategy. Specifically, guidelines strongly recommend the use of ticagrelor because it has demonstrated excellent performance in reducing the incidence of ischemic adverse events in this patient group, which has been supported by extensive clinical research [6,23,24]. The Platelet inhibition and Patient Outcomes (PLATO) study demonstrated that, compared with clopidogrel, ticagrelor treatment in ACS patients after PCI can further reduce the occurrence of thrombotic events (including cardiovascular death, MI, and stroke) without increasing the incidence of bleeding events [25]. However, for East Asian patients, while ticagrelor is effective in mitigating ischemic events and mortality, it is associated with a higher relative risk of bleeding [26]. Therefore, when formulating a DAPT strategy for East Asian patients at discharge, it is crucial to carefully balance the risks of bleeding and ischemia to achieve optimal therapeutic outcomes.
According to the latest clinical guidelines, the GRACE risk score is an important tool for assessing the risk of patients with ACS after PCI [2,16,27,28]. A large-scale real-world study in China has revealed that the selection of P2Y12 inhibitors can be optimized based on risk stratification of the GRACE score. The data showed that in patients with low GRACE scores, ticagrelor was associated with a higher bleeding risk compared with clopidogrel, whereas in intermediate-to-high risk populations, it was associated with reduced ischemic events without an increased risk of bleeding [29]. However, relying solely on the GRACE score for guiding the selection of P2Y12 inhibitors may overlook the influence of the CYP2C19 genotype and the interindividual variations in the effectiveness of clopidogrel. A substantial body of evidence has demonstrated that variations in the CYP2C19 genotype have a significant impact on the efficacy of clopidogrel, particularly in patients with intermediate or poor metabolizer status. In these patients, the standard dose of clopidogrel may be associated with an increased risk of adverse cardiovascular events [[30], [31], [32]]. A retrospective study in South Korea corroborated these findings, demonstrating that patients with intermediate or poor metabolizer CYP2C19 genotypes exhibited a markedly elevated risk of major cardiovascular outcomes (including cardiac death, MI, and stent thrombosis) over 5 years compared with normal/rapid metabolizers [33]. A prospective, multicenter, nonrandomized controlled clinical study in the United States utilizing CYP2C19 genotype to guide antiplatelet therapy has shown that for patients carrying LOF gene variants, the use of prasugrel/ticagrelor as an alternative treatment significantly reduces the risk of atherosclerotic thrombotic events in comparison with clopidogrel. Furthermore, the study found that there was no increase in the incidence of bleeding events between the groups, regardless of whether patients carried the LOF allele [34]. These findings align with previous nonrandomized studies, small experiments, and meta-analyses, which collectively demonstrate the efficacy of genotype-guided treatment strategies in reducing the risk of atherosclerotic thrombotic events. The present study showed that the proportion of patients carrying CYP2C19 LOF alleles reached 50% to 60%, consistent with previous reports [[35], [36], [37], [38]].
Both the GRACE score and the CYP2C19 genotype are valuable tools for guiding DAPT in patients with ACS who have undergone PCI. Although the GRACE scoring system does not incorporate information on CYP2C19 genotype, a retrospective cohort study conducted in China demonstrated that integrating the CYP2C19 genotype with the GRACE score provides a more accurate prediction of the long-term risk of major adverse cardiovascular events in ACS patients treated with clopidogrel after PCI [39]. However, the study was limited by its small sample size and the absence of prospective validation, which may constrain the generalizability of its findings [39]. Therefore, developing personalized antiplatelet treatment plans based on the patient’s clinical characteristics and genotype may be a key strategy to improve the safety and efficacy of treatment for ACS patients after PCI. The present real-world study indicates that among patients with ACS who carry CYP2C19 LOF alleles and undergo PCI, clopidogrel may be a more appropriate choice for patients with low GRACE scores, as it reduces clinically significant bleeding events while maintaining ischemic risk at levels similar to ticagrelor. In patients with intermediate to high GRACE scores, ticagrelor use was associated with a lower ischemic risk without a significant increase in bleeding risk. Moreover, for patients without the CYP2C19 LOF alleles, regardless of their GRACE score, clopidogrel and ticagrelor show similar results in terms of bleeding and ischemic risks [40]. These findings emphasize the importance of considering both GRACE scores and CYP2C19 genotypes in the decision-making process regarding antiplatelet therapy.
For patients with ACS undergoing PCI, postoperative secondary prevention strategies are crucial. Accurate risk stratification enables a comprehensive evaluation of patients’ prognoses and risk levels, allowing for the development of individualized treatment plans tailored to each patient’s specific risk profile. This early and thorough risk classification significantly enhances the prognosis of high-risk ACS patients while alleviating the treatment burden for low-risk individuals, thereby facilitating more optimized and personalized care.
The present study has several limitations. First, as a retrospective observational study, there is a possibility of unavoidable experimental bias. Despite the use of PSM to adjust for confounding factors between the 2 groups, the possibility of unmeasured bias remains. Accordingly, future multicenter randomized controlled trials may further validate our findings. Second, the sample size is limited to Chinese patients. Given the “East Asian Paradox,” which gives rise to discrepancies in the prevalence of CYP2C19 LOF alleles, our findings may be more pertinent to the East Asian population. Therefore, further research is necessary to ascertain their applicability to other ethnic groups. Third, the participants in this study were exclusively ACS patients treated with PCI, limiting the external validity of our results to those receiving only drug treatment, coronary artery bypass grafting, or alternative therapies for ACS. Fourth, as an observational study, our research is susceptible to potential confounding by indication. The selection of P2Y12 inhibitors (clopidogrel or ticagrelor) was based solely on clinicians’ individualized assessments (primarily considering the balance of bleeding/ischemic risks and comorbidities). Fifth, our study was underpowered for rare outcomes like stroke, especially in subgroups with a wide CI (stroke HR, 0.18; 95% CI, 0.04-0.82), reflecting substantial uncertainty. Importantly, during the study period, CYP2C19 genotyping was not routinely available for clinical decision-making; thus, treatment selection was neither genotype-guided nor randomized. Lastly, we did not assess adverse reactions, such as dyspnea, which are common reasons for discontinuing ticagrelor. Future studies need to take these factors into account so that the efficacy and safety of antiplatelet therapy can be more fully assessed.
5. Conclusion
This real-world study suggested that for ACS patients carrying CYP2C19 LOF alleles who undergo PCI, the GRACE score may help stratify the risk of ischemic and bleeding events. Stratification of the GRACE score allows for the selection of the most suitable potent P2Y12 inhibitors for patients to maximize their therapeutic benefits. The findings of the study lend support to the preferential use of clopidogrel in patients with low GRACE scores, with the aim of reducing the incidence of bleeding events and adverse reactions that may be associated with potent P2Y12 inhibitors. For patients with intermediate to high GRACE scores, ticagrelor showed a potential signal of reduced ischemic events (particularly stroke; n = 2 events in ticagrelor group), though the small number of events necessitates cautious interpretation and requires validation in larger multicenter studies.
Acknowledgments
Funding
The study was supported by the National Key Research and Development Program of China (2022YFC2503503 and 2023JH2/101700126).
Author contributions
D.D.: Writing – original draft, Writing – review and editing, Investigation. J.L.: Writing – review and editing, Investigation, Methodology, Conceptualization. Y.L.: Writing – review and editing, Investigation, Methodology, Project administration, Conceptualization. M.Q.: Writing – review and editing, Investigation, Data curation. B.W.: Writing – review and editing, Investigation, Methodology, Conceptualization. B.Q.: Writing – review and editing, Investigation, Methodology, Conceptualization. Y.H.: Writing – review and editing, Supervision, Methodology, Investigation, Conceptualization.
Relationship disclosure
There are no competing interests to disclose.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Footnotes
Handling Editor: Dr Vania M. Morelli
The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2025.102997
Supplementary material
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Associated Data
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Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.